Summary: Age-related macular degeneration (AMD) represents the most common cause of blindness in patients over the age of 60. While both hereditary and environmental factors appear to play a role in the pathogenesis of the disease, no common genetic mutations have been identified. Based on laboratory evidence, one proposed hypothesis for this disease focuses on an altered injury response program of the retinal pigment epithelium. A clinical trial has now been completed which is testing this hypothesis that patterns of gene expression involved in wound repair, cell injury and death are altered in the eyes of patients with AMD and these genetic alterations can be detected in peripheral sites other than the eye. Biopsied skin fibroblasts from 7 patients with various forms of age-related macular degeneration and 3 age-matched control patients were obtained, grown in culture and exposed to a sublethal oxidative stress. RNA from these cells were examined and differential expression of a 15,000 genes was analyzed using a gene chip. Results were confirmed by quantitative RT-PCR. The results indicate a marked difference in gene expression profile between these groups of patients. Specifically, patients with more severe forms of AMD had a greater disregulation of affected compared with minimally affected and age-matched control patients. These results indicate that an abnormal response to injury may play a role in the pathogenesis of AMD. This study is now being extended to examine retinal pigment epithelial cells from autopsy specimens from aged eyes. Biopsies are being taken of these eyes and electron microscopic confirmation of the presence or absence of age-related macular degeneration changes is being performed. As above, sublethal injury is initiated and both a microarray analysis as well as a proteomic analysis of the differences between age-matched control and affected cells is being initiated. This is the first study of its kind to study so extensive the genetic responses of RPE cells taken when the diagnosis of AMD has been confirmed by the gold standard of accuracy, electron microscopy.